Expression and targeting of the apoptosis inhibitor, survivin, in human melanoma

The newly described apoptosis inhibitor survivin is expressed in many human cancers and appears to play a critical part in both apoptosis regulation a nd cell cycle progression. Its potential role in malignant melanoma is unkn own, In a panel of 30 malignant melanomas, survivin was strongly expressed in all cases (15 of 15) of metastatic malignant melanomas and 13 of 15 case s of invasive malignant melanomas by immunohistochemistry. In invasive mali gnant melanomas, survivin was also expressed in the in-situ component of th e lesion. Survivin expression was found in all cases (11 of 11) of nevi, bu t not in melanocytes in sections of normal skin. The apoptosis inhibitor bc l-2 was expressed in 26 of 30 cases, but generally at lower levels than tha t of infiltrating lymphocytes. The mitotic index, as assessed by MIB-1 stai ning, was consistently higher in metastatic than invasive malignant melanom as. Assessment of apoptotic index by in situ end-labeling revealed extremel y low rates of apoptosis in most malignant melanomas. Survivin expression b y western blotting was detected in four human metastatic malignant melanoma cell lines but not in cultured normal human melanocytes. Transfection of b oth YUSAC-2 and LOX malignant melanoma cells with green fluorescence protei n-conjugated survivin anti-sense or green fluorescence protein-conjugated s urvivin dominant negative mutant (Cys85Ala) resulted in increased apoptosis in the absence of other genotoxic stimuli, Two-color flow cytometry confir med that YUSAC-2 cells transfected with survivin anti-sense expressed less endogenous survivin and exhibited an increased fraction of cells with sub-G (1) DNA content. These data demonstrate that apoptosis inhibition by surviv in may participate in the onset and progression of malignant melanomas, and suggest that therapeutic targeting of survivin may be beneficial in patien ts with recurrent or metastatic disease.